Hyperventilation and Oxygenation to Prolong Breath Hold in Breast Cancer Irradiation Treatment

Radiotherapy (RT) has an established role in breast cancer, complementing surgery and systemic therapies to prevent recurrences and improve survival. Long-Term follow-up shows that the beneficial effect on survival is weakened by radiation-induced cardiac and lung cancer mortality, especially in patients with left sided breast cancer or requiring irradiation of regional lymph nodes. Cardiac toxicity is of major concern because many patients receive cardiotoxic systemic treatments like anthracyclines and trastuzumab. Dose and volume of the heart exposed to radiation correlate with severity of cardiac toxicity. The heart dose-volume parameters are highest for patients receiving left-side radiotherapy especially if irradiation of the internal mammary lymph nodes is performed. Risk of (fatal) ischemic heart attack increases linearly with mean heart dose with no known dose threshold. In patients who receive left-side local treatment, heart dose is decreased by using prone positioning or deep-inspiration breath hold (DIBH), or a combination of both.

Previous research has shown that the heart shifts to an anatomical more favorable position in DIBH, away from the breast, chest wall and internal mammary lymph nodes, reducing heart dose. This advantage remains in prone positioning. The goal is to prolong the duration of a single DIBH, to create a long-DIBH (L-DIBH). Possible advantages are better positioning of the patient, execution of technically more difficult procedures and inclusion of regional lymph node (locoregional) irradiation. Most patients can't sustain a DIBH long enough to perform simulation with computed tomography (CT) and delineation during DIBH, so delineation of the laser lines during CT-simulation is performed on the shallow breathing (SB) scan. During positioning of the patient on the radiotherapy machine, a daily cone-beam CT (CBCT) is performed. The duration of this CBCT is 40 seconds, maintaining DIBH during this period is also hard for most patients. So currently the positioning at the moment of treatment is based on the SB CT-scan, whilst the DIBH CT-scan is used for treatment. This could potentially induce suboptimal positioning. Breath hold during CBCT positioning and CT-simulation and delineation could minimize shifts in treatment position. The current DIBH schedules for whole breast cancer radiotherapy without inclusion of the lymph nodes, use between three and six DIBHs of 12 to 18 seconds. Longer DIBH could lead to less DIBHs and faster treatment execution, which is especially important when the lymph nodes are included in the target volumes. Locoregional irradiation, including the lymph nodes, requires between 10 and 14 DIBHs of 15-30 seconds which leads to a total treatment time of around 5 minutes. This represents a substantial physical and mental effort for all but the most able patients.

This research, the first phase of the Hyperventilation Oxygenation Breath hold in Breast cancer Irradiation Treatment (HOBBIT) trail, will focus on finding a technique to assist patients to maintain a long DIBH (L-DIBH) during radiotherapy. Other research has shown a potential increase in duration of breath hold and reduction in rest time between DIBHs using oxygen in combination with hyperventilation. There is a safe way to prolong DIBH to at least 5 minutes. However, the technique requires a long training period for the patient, and 15 minutes of mechanical ventilation before each treatment session, making the technique very time consuming and resource intensive. The investigators hope to simplify the technique by allowing patients to do multiple L-DIBHs during the 5 minutes of treatment time. The investigators found from preliminary tests that using shorter L-DIBHs has several advantages, firstly pre-oxygenation and induction of hypocapnia can be achieved in a shorter time, secondly the duration of training is reduced, and thirdly a the costs are reduced.

Increase in blood pressure is the main risk of L-DIBH. No adverse events of L-DIBH have been reported. In order to minimize the risks during testing, this research project was developed in collaboration with the anesthesiology department, to ensure safety of the participants during L-DIBH. For all subjects, vital parameters will be continuously monitored by medical staff. Safety boundaries are in place which subjects are not allowed to cross during L-DIBH.

The aim of this research is to develop a new and easy technique for L-DIBH in prone and supine position, feasible for daily use at our radiotherapy department. The purpose of the technique is to allow locoregional treatment using a reasonable amount of L-DIBHs, increase patient positioning and accuracy of radiation treatment, and further significantly reduce heart toxicity for left sided cancer patients. The HOBBIT trial includes multiple phases. The first phase is performed on healthy volunteers, different support techniques to prolong DIBH will be tested. In the second phase the most optimal techniques to perform a L-DIBH will be validated on breast cancer patients. Around 40 volunteers will be included in the first phase of the HOBBIT trail, the final amount of volunteers depends on the amount of testing needed to find a technique which fulfills all criteria for phase two. The second phase of the HOBBIT trail will include breast cancer patients treated at our radiotherapy center. The expectations from previous research is that the investigators will see a similar increase in DIBH time, compared to healthy volunteers. The final goal is the use of the technique during locoregional radiation therapy at the University Hospital of Ghent.

Inclusion criteria

• Female
• Volunteer
• Age ≥ 18 years
• Karnofsky index of at least 90
• Single DIBH of at least twenty seconds without assistance
• Informed consent obtained, signed and dated before specific protocol procedures

Exclusion criteria

• Pregnant women
• Volunteers above WHO Obesity class II (BMI>35kg/m²)
• Subjects on oxygen treatment during day or night
• COPD or Asthma patients
• Volunteers with pulmonary hypertension
• New York Heart Association functional classification (NYHA) of 2 or less
• Personal history of cerebrovascular disease, aortic disease, coronary artery disease or myocardial disease
• Treatment with antihypertensive medication
• Missing more than three teeth without use of a prosthesis
• Gastric tube present
• Smoking
• Previous breath-holding experience (e.g. diver, etc.)
• Anxiety symptoms grade 1 or higher according to CTCAE v.5
• Mental condition rendering the volunteer unable to understand the nature, scope and possible consequences of the study